Positional Identification of RT1-B (HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis

Abstract

Rheumatoid arthritis (RA) is associated with amino acid variants in multiple MHC molecules. The association to MHC class II (MHC-II) has been studied in several animal models of RA. In most cases these models depend on T cells restricted to a single immunodominant peptide of the immunizing Ag, which does not resemble the autoreactive T cells in RA. An exception is pristane-induced arthritis (PIA) in the rat where polyclonal T cells induce chronic arthritis after being primed against endogenous Ags. In this study, we used a mixed genetic and functional approach to show that RT1-Ba and RT1-Bb (RT1-B locus), the rat orthologs of HLA-DQA and HLA-DQB, determine the onset and severity of PIA. We isolated a 0.2-Mb interval within the MHC-II locus of three MHC-congenic strains, of which two were protected from severe PIA. Comparison of sequence and expression variation, as well as in vivo blocking of RT1-B and RT1-D (HLA-DR), showed that arthritis in these strains is regulated by coding polymorphisms in the RT1-B genes. Motif prediction based on MHC-II eluted peptides and structural homology modeling suggested that variants in the RT1-B P1 pocket, which likely affect the editing capacity by RT1-DM, are important for the development of PIA.

Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis

“…1) were less susceptible to PIA, we observed a small but reproducible difference in arthritis protection between these two strains from day 14 to day 25 ( Fig. 2A) (21). This observation suggested a putative second QTL in the nonclassical MHC-Ib and/or the MHC-III region, which was confirmed with the recombinant strain DA.1HR7, which carries a fragment from DA.1HR2 in the MHC-Ib/MHC-III region ( Fig.…”

“…The prefixes "HR," "UR," and "FR" indicate that the congenic fragments originate from DA.1H (RT1 h haplotype), DA.1U (RT1 u haplotype), and DA.1F (RT1 f haplotype), respectively (Materials and Methods). PIA has been previously reported in DA.1HR2, DA.1HR61, DA.1HR62, DA.1HR83, DA.1FR2, DA.1FR9, and DA.1UR2 rats (21,22). The MHC arthritis QTLs Ltab-Ncr3 and RT1-B (previously identified) (21), are shaded in brown.…”

“…We previously identified RT1-B in the MHC-II region as a susceptibility locus for acute PIA and excluded a contribution of the classical MHC-Ia region (21). Although rats of both the MHC congenic strain DA.1HR2, which spans the entire MHC, and the MHC-II congenic strain DA.1HR61 ( Fig.…”

“…We recently established a panel of recombinant strains in the MHC region to study the MHC association with T-cell selection (22) and showed that RT1-B (the human ortholog is HLA-DQ) in MHC-II determines the onset and severity of PIA (21). Here, we constructed a panel of recombinant strains in MHC-III to study the association of MHC-III with arthritis on the DA (RT1 av1 ) background.…”

“…Animal models for RA are attractive alternatives to human association studies for gene identifications because the use of these models not only overcomes genetic heterogeneity and reduces environmental effects but also allows the isolation of specific genetic regions to study their roles in RA in vivo (14)(15)(16). Rat arthritis models such as pristane-induced arthritis (PIA) (17,18), which meet many of the criteria for the diagnosis of RA (19), have been used to reveal highly significant linkages to unique chromosomal regions, often a much smaller interval with far fewer genes than previously postulated for quantitative traits (16,20,21).…”